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Induction of stem cell factor/c-Kit/slug signal transduction in multidrug-resistant malignant mesothelioma cells

Alfonso Catalano1, Sabrina Rodilossi, Maria Rita Rippo

  • 1Department of Molecular Pathology and Innovative Therapies, Polytechnic University of Marche, Ancona 60131, Italy. catgfp@yahoo.it

The Journal of Biological Chemistry
|September 1, 2004
PubMed

Insights

Malignant mesothelioma cells resist chemotherapy through a newly identified pathway involving stem cell factor (SCF) and c-Kit, which increases Slug expression and chemoresistance. Targeting this SCF/c-Kit/Slug pathway may overcome drug resistance in mesothelioma patients.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Signaling

Background:

  • Malignant mesothelioma (MM) exhibits significant resistance to conventional chemotherapy, with underlying mechanisms largely unknown.
  • Cytokine and growth factor signaling pathways are implicated in MM progression and survival.

Purpose of the Study:

  • To identify novel signaling pathways contributing to multidrug resistance (MDR) in malignant mesothelioma (MM) cells.
  • To investigate the role of the stem cell factor (SCF)/c-Kit/Slug pathway in mediating MM chemoresistance.

Main Methods:

  • Comparative gene expression profiling of MM cells and their multidrug-resistant (MM DX) sublines.
  • Small interfering RNA (siRNA) knockdown of c-Kit and Slug in MM DX cells.
  • Transfection of parental MM cells with c-Kit in the presence of SCF.

Main Results:

  • MM DX cells showed increased expression of SCF, c-Kit, and Slug mRNA compared to parental MM cells.
  • Knockdown of c-Kit or Slug sensitized MM DX cells to apoptosis induced by doxorubicin, paclitaxel, and vincristine.
  • Overexpression of c-Kit with SCF in parental MM cells upregulated Slug and conferred chemoresistance.

Conclusions:

  • Autocrine SCF/c-Kit signaling upregulates Slug, conferring broad-spectrum chemoresistance in malignant mesothelioma.
  • The SCF/c-Kit/Slug pathway represents a novel therapeutic target for overcoming drug resistance in MM.
  • This pathway offers potential for pharmacological or genetic interventions in MM patients.

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